MD-224

MD-224 is a first-in-class and highly potent small-molecule human murine double minute 2 (MDM2) degrader based on the proteolysistargeting chimera (PROTAC) concept. MD-224 induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells, and achieves an IC50 value of 1.5 nM in inhibition of growth of RS4;11 cells. MD-224 has the potential to be a new class of anticancer agent[1].

Research Areas >> Cancer

Signaling Pathways >> Apoptosis >> MDM-2/p53

Signaling Pathways >> PROTAC >> PROTAC

MD-224 (1-30 nM; 2 hours) effectively induces depletion of MDM2 protein and concurrently accumulation of p53 protein in a dose-dependent manner in RS4;11 cells[1]. MD-224 (30 nM; 6 hours) is more potent than MI-1061 in induction of transcriptional upregulation of these p53 target genes but have no effect on TP53 itself in RS4;11 cells[1]. MD-224 (0.001-1 μM; 24hours) induces robust apoptosis at ≤10 nM in a dose-dependent manner upon a 24 hours treatment[1]. Western Blot Analysis[1] Cell Line: RS4;11 cells Concentration: 1 nM; 3 nM; 10 nM; 30 nM Incubation Time: 2 hours Result: Decreased MDM2 protein and accumulated of p53 protein. RT-PCR[1] Cell Line: RS4;11 cells Concentration: 30 nM Incubation Time: 6 hours Result: Upregulated p53 target gene expression. Apoptosis Analysis[1] Cell Line: RS4;11 cells Concentration: 0.001 μM, 0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM Incubation Time: 24 hours Result: Induces robust apoptosis in RS4;11 cells.

[1]. Li Y, et al. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis TargetingChimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable TumorRegression. J Med Chem. 2019 Jan 24;62(2):448-466